Testosterone therapy increases the anticoagulant potential in men with opioid-induced hypogonadism: a randomized, placebo-controlled study

Abstract

Introduction: Hypogonadism is prevalent during opioid treatment, and low testosterone concentrations are associated with cardiovascular disease. The effect of testosterone replacement therapy (TRT) on the coagulation system in men with hypogonadism is not clarified. We investigate the effects of TRT on the tissue factor (TF) and contact activation pathways of coagulation in opioid-treated men.

Materials and methods: This was a double-blinded, placebo-controlled study in 37 men with total testosterone < 12 nmol/L randomized to 24 weeks of testosterone injections (n = 17) or placebo (n = 20). Variables of the coagulation system were analysed at baseline and after 24 weeks. Measurements included the TF pathway (endogenous thrombin potential (ETP) and peak thrombin), the contact activation pathway (endogenous kallikrein potential (EKP) and peak kallikrein), coagulation factors (FVII, FX, prothrombin, and FXII), and inhibitors (tissue factor pathway inhibitor (TFPI), protein C, protein S, antithrombin, and C1 esterase inhibitor (C1inh)). Between-group differences at 24 weeks were determined with analysis of covariance. Within-group changes in TRT and placebo were analysed with paired t-test.

Results: Between-group differences at 24 weeks were observed for ETP (P = 0.036), FVII (P = 0.044), FX (P = 0.015), prothrombin (P = 0.003), protein C (P = 0.004), and protein S (P = 0.038). Within the TRT group, ETP, peak thrombin, FVII, FX, prothrombin, TFPI, protein C, FXII, and C1inh decreased and protein S increased (all P < 0.05). Within the placebo group, coagulation outcomes were unchanged.

Conclusion: TRT affects the coagulation system in an anticoagulant direction through suppressed TF pathway in men with opioid-induced hypogonadism.

Keywords: blood coagulation; hormone therapy; hypogonadism; testosterone; thrombin generation.

Figure 1

Coagulation system. TF, tissue factor; F, coagulation factor (e.g. FVII); TFPI, tissue factor pathway inhibitor; C1inh, C1 esterase inhibitor; TAT, thrombin–antithrombin complexes; vWF, von Willebrand factor. The letter ‘a’ denotes activated enzymes. Solid lines indicate activation, dashed lines inhibition, and dashed grey lines indicate thrombin-induced feedback activation.

Figure 2

Measures of generation of thrombin and kallikrein generation. Endogenous thrombin potential, peak thrombin concentration, endogenous kallikrein potential, and peak kallikrein concentration at baseline and after 24 weeks of testosterone replacement therapy or placebo. Results are presented as mean ± s.d.